Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature.
Li-Wei LiuYao-Yu HsiehPei-Ming YangPublished in: Journal of personalized medicine (2020)
Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell-cell and cell-extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future.
Keyphrases
- single cell
- copy number
- extracellular matrix
- genome wide
- wild type
- cell therapy
- small cell lung cancer
- papillary thyroid
- squamous cell carcinoma
- oxidative stress
- end stage renal disease
- sars cov
- poor prognosis
- newly diagnosed
- risk assessment
- young adults
- mesenchymal stem cells
- emergency department
- cell proliferation
- bone marrow
- tyrosine kinase
- functional connectivity
- human health
- resting state
- drug induced
- transcription factor
- genome wide analysis
- patient reported
- data analysis
- replacement therapy